Cancer is a common and more
frequent problem in older persons.[1,2] Currently, about 50% of breast cancer cases occur in women aged 65
years and older. Illnesses that were disabling and often fatal in the past are
now treated effectively, and people are living longer. Treatments for cancer are
also evolving, and prolonging the lives of cancer patients is now possible for
many malignancies, including breast cancer.
The incidence of breast cancer in the United States has begun to
decrease. Mortality rates have also been decreasing in recent years, and
with increased use of mammographic screening, breast cancers are being detected
at earlier, more curable stages. Moreover, adjuvant therapies have become more
successful, and new drugs (such as the taxanes) have improved response rates and
tolerability of therapy for patients with metastatic disease.
Regardless of age, the treatment of breast cancer involves
complex decisions about risks vs benefits for each patient. As age increases,
the number of comorbidities increases, making the potential risks of systemic
therapy greater and the potential benefits smaller. Preventing breast cancer and
its recurrence and/or progression, however, becomes more important as we are
able to help people with many diseases live longer.
This article will discuss the use of hormonal therapy and
chemotherapy in older women. There is no unanimously accepted definition of
"older," but most clinicians consider patients aged 65 years and over
to be in this category.
The incidence of breast cancer increases with age. Potential
strategies to decrease the risk of breast cancer in the geriatric population
include changes in life-style such as increasing exercise, dietary modifications
such as following a low-fat diet, and drug therapy with selective
estrogen-receptor modulators. The data suggesting that life-style and dietary
changes may lower breast cancer risk are controversial and far from compelling.
Since most women with breast cancer are likely to die of other causes, exercise
and dietary modification are prudent recommendations for most patients,
irrespective of breast cancer risk.
At present, the use of selective estrogen-receptor modulators is
the most exciting option for breast cancer prevention. These agents include
tamoxifen (Nolvadex), raloxifene (Evista), and toremifene (Fareston). Only
tamoxifen has been approved by the Food and Drug Administration (FDA) to
decrease the incidence of breast cancer. Raloxifene has been approved for the
treatment of osteoporosis, and preliminary data suggest that it may also
significantly decrease the incidence of breast cancer.[7,8]
Trials of Tamoxifen
Three published trials have evaluated the potential preventive
benefit of tamoxifen: the National Surgical Adjuvant Breast and Bowel Project
Prevention trial (NSABP P-1), the Royal Marsden Hospital chemoprevention
trial, and an Italian randomized trial in women who had undergone a
hysterectomy (Table 1). The major differences between these trials have been
discussed in detail elsewhere. The NSABP P-1 trial was the only one of the
three with a large cohort of older women. It showed a 50% reduction in the
incidence of invasive and noninvasive breast cancer among women who took
NSABP P-1 Trial: In NSABP P-1, 30% of participants were 60
years of age and older and 6% were over the age of 70 years. Women with a
1.67% risk of developing breast cancer within 5 years were eligible for the
trial. All women aged 60 years or older in the United States meet these
criteria, irrespective of other risk factors. Tamoxifen lowered the incidence of
both in situ and invasive lesions. There was a 55% reduction in the incidence of
invasive breast cancer associated with tamoxifen use in older women; the 5-year
probability of invasive breast cancer developing in women 60 years of age and
older decreased from almost 4% to about 2%.
This effect was limited to estrogen-receptor (ER)-positive
invasive tumors; ER-negative tumors were found with similar frequency in the
tamoxifen and placebo-treated groups. Risks associated with the use of tamoxifen
in older women included a significantly higher incidence of endometrial cancer
and thromboembolic events. In addition, tamoxifen use increased the frequency of
vasomotor and gynecologic symptoms and problems with sexual function.
Royal Marsden Hospital Trial: The Royal Marsden Hospital
chemoprevention trial included women at increased risk of breast cancer based on
family history. As such, the majority of women in this trial (61%) were
younger than age 50 years; women over age 70 years were ineligible. At a median
follow-up of 70 months, the use of tamoxifen did not decrease the incidence of
Italian Trial: The Italian randomized trial included any
woman who had undergone a hysterectomy. Approximately one-third of women in
the Italian trial were over age 55 years, and only 11.7% were age 60 or older;
women over age 70 were ineligible. No decrease in the incidence of breast cancer
was associated with the use of tamoxifen, but women in this trial were at lower
risk for breast cancer compared to women in the other two reported trials.
Both the Royal Marsden Hospital chemoprevention trial and the
Italian randomized trial allowed women who were taking hormone replacement
therapy to participate. In the Italian trial, the rate of breast cancer was
lower among women taking hormone replacement therapy plus tamoxifen than in the
cohort taking replacement therapy alone (log rank P = .0216). This is not
currently accepted practice in the United States.
Trials of Raloxifene
Raloxifene is another selective estrogen-receptor modulator with
a toxicity profile similar to tamoxifen that allegedly causes fewer endometrial
changes. In the Multiple Outcomes of Raloxifene (MORE) trial, 7,705 women
with osteoporosis were randomly assigned to receive one of two different doses
of raloxifene or placebo for 3 years. Participants were primarily white (95%)
and over age 62 years (82%). At 40 months of follow-up, women taking raloxifene
had 43% fewer vertebral fractures and a 76% lower incidence of invasive breast
The rate of breast cancer for all arms of this trial was low
(10.5 per 1,000 women given placebo and 2.5 per 1,000 women given raloxifene),
but the difference was still statistically significant (response rate [RR] =
0.24; 95% confidence interval [CI] = 0.13-0.44). Hormone-receptor-positive
tumors were preferentially prevented, and thrombotic events were more prevalent
in women receiving raloxifene in this trial as well, but no increase in
endometrial cancer was seen.
A second prevention trial (NSABP P-2) comparing tamoxifen with
raloxifene, the STAR trial, is underway. Targeted accrual is approximately
22,000 postmenopausal women.
Calculating Breast Cancer Risk
All women over age 60 years were eligible for NSABP P-1 based on
their calculated risk of breast cancer. Breast cancer risk assessment is
becoming a routine part of general medical care, and many women are reviewing
the risks and benefits of "preventive" tamoxifen with their doctors.
The risk of developing breast cancer can be easily calculated using the Gail
model. An updated version of this risk assessment tool is available on the
Internet at http://cancertrials.nci.nih.gov.
Moreover, Gail and his colleagues have recently provided
detailed clinical data on how to calculate the potential benefits and risks of
tamoxifen therapy, factoring in available epidemiologic data on the risks of
thromboembolic complications and endometrial cancer (Table 2). For example,
in a 65-year-old white woman with an intact uterus and a thromboembolic risk
similar to that of patients in the NSABP P-1 trial, the 5-year risk of invasive
breast cancer needs to exceed 7.0% in order for the benefits of tamoxifen
therapy to outweigh the risks. The benefits of tamoxifen would outweigh the
risks in the same woman who had a hysterectomy and whose risk was 3.5%.
In older women, the preventive benefits of tamoxifen may
outweigh the risks, but these women should be counseled about the risks and
benefits of preventive tamoxifen. They should also be encouraged to participate
in the STAR trial.
1. Greenlee RT, Murray T, Bolden S, et al: Cancer statistics,
2000. CA Cancer J Clin 50:7-33, 2000.
2. Satariano WA, Ragland DR: The effect of comorbidity on 3-year
survival of women with primary breast cancer. Ann Intern Med 120:104-110, 1994
3. McKean-Cowdin R, Feigelson HS, Ross RK, et al: Declining
cancer rates in the 1990s. J Clin Oncol 18:2258-2268, 2000
4. Chu KC, Tarone RE, Kessler LG, et al: Recent trends in US
breast cancer incidence, survival, and mortality rates. J Natl Cancer Inst
5. Landis SH, Murray T, Bolden S, et al: Cancer statistics,
1999. CA Cancer J Clin 49:8-31, 1999.
6. Jordan VC, Morrow M: Tamoxifen, raloxifene, and the
prevention of breast cancer. Endocr Rev 20:253-278, 1999.
7. Ettinger B, Black DM, Mitlak BH, et al: Reduction of
vertebral fracture risk in postmenopausal women with osteoporosis treated with
raloxifene. JAMA 282:637-645, 2000.
8. Cummings SR, Eckert S, Krueger KA, et al: The effect of
raloxifene on risk of breast cancer in postmenopausal women: Results from the
MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA
9. Fisher B, Costantino JP, Wickerham L, et al: Tamoxifen for
prevention of breast cancer: Report of the National Surgical Adjuvant Breast and
Bowel Project P-1 study. J Natl Cancer Inst 90:1371-1388, 1998.
10. Powles T, Eeles R, Ashley S, et al: Interim analysis of the
incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised
chemoprevention trial. Lancet 352:98-101, 1998.
11. Veronesi U, Maisonneuve P, Costa A, et al: Prevention of
breast cancer with tamoxifen: Preliminary findings from the Italian randomised
trial among hysterectomised women. Italian Tamoxifen Prevention Study. Lancet
12. Lippman SM, Brown PH: Tamoxifen prevention of breast cancer:
An instance of the fingerpost. J Natl Cancer Inst 91:1809-1819, 1999.
13. Day R, Ganz PA, Costantino JP, et al: Health-related quality
of life and tamoxifen in breast cancer prevention: A report from the National
Surgical Adjuvant Breast and Bowel Project P-1 Study. J Clin Oncol 17:2659-2669,
14. Cummings SR, Norton L, Eckert S, et al: Raloxifene reduces
the risk of breast cancer and may decrease the risk of endometrial cancer in
post-menopausal women. Two-year findings from the Multiple Outcomes of
Raloxifene Evaluation (MORE) Trial (abstract). Proc Am Soc Clin Oncol 17:2,
15. Gail MH, Costantino JP, Bryant J, et al: Weighing the risks
and benefits of tamoxifen treatment for preventing breast cancer. J Natl Cancer
Inst 91:1829-1846, 1999.
16. Early Breast Cancer Trialists’ Collaborative Group:
Polychemotherapy for early breast cancer: An overview of the randomized trials.
Lancet 352:930-942, 1998.
17. Early Breast Cancer Trialists’ Collaborative Group:
Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet
18. Fisher B, Redmond C, Wolmark N, et al: Disease-free survival
at intervals during and following completion of adjuvant chemotherapy: The NSABP
experience from three breast cancer protocols. Cancer 48:1273-1280, 1981.
19. Clark GM: Prognostic and predictive factors, in Harris JR,
Lippman ME, Morrow M, et al (eds): Diseases of the Breast (2nd ed), pp 489-514.
Philadelphia, Lippincott Williams & Wilkins, 2000.
20. Lyman GH, Lyman S, Balducci L, et al: Age and the risk of
breast cancer recurrence. Cancer Control 3:421-427, 1996.
21. Diab SG, Elledge RM, Clark GM: Tumor characteristics and
clinical outcome of elderly women with breast cancer. J Natl Cancer Inst
22. US Department of Health and Human Services: Health United
States 1996-7 and Injury Chartbook. DHHS Publication No. (PHS) 97-1232, 1997.
23. Extermann M, Balducci L, Lyman GH: What threshold for
adjuvant therapy in older breast cancer patients? J Clin Oncol 18:1709-1717,
24. Welch HG, Albertsen PC, Nease RF: Estimating treatment
benefits for the elderly: The effect of competing risks. Ann Intern Med
25. Fish EB, Chapman JA, Link MA: Competing causes of death for
primary breast cancer. Ann Surg Oncol 5:368-375, 1998.
26. Satariano WA, Ragheb NE, Dupuis MA: Comorbidity in older
women with breast cancer: An epidemiologic approach, in Yancik R, Yates J (eds):
Cancer in the Elderly: Approaches to Early Detection and Treatment, pp 71-107.
New York, Springer, 1989.
27. Satariano WA: Aging, comorbidity, and breast cancer
survival: An epidemiologic view. Adv Exp Med Biol 330:1-11, 1993.
28. Desch CE, Hillner BE, Smith TJ, et al: Should the elderly
receive chemotherapy for node-negative breast cancer? A cost-effectiveness
analysis examining total and active life-expectancy outcomes. J Clin Oncol
29. Mandelblatt JS, Yabroff KR: Effectiveness of interventions
designed to increase mammography use: A meta-analysis of provider-targeted
strategies. Cancer Epidemiol Biomarkers Prev 8:759-767, 1999.
30. Anonymous: Tamoxifen for early breast cancer: An overview of
the randomized trials. Early Breast Cancer Trialists’ Collaborative Group.
Lancet 351:1451-1467, 1998.
31. Von Hoff DD, Layard MW, Basa P, et al: Risk factors for
doxorubicin-induced congestive heart failure. Ann Intern Med 91:710-717,
32. Rivkin SE, Green S, Metch B, et al: Adjuvant CMFVP vs
tamoxifen vs concurrent CMFVP and tamoxifen for postmenopausal, node-positive,
and estrogen receptor-positive breast cancer patients: A Southwest Oncology
Group study. J Clin Oncol 12:2078-2085, 1994.
33. Pritchard KI, Paterson AH, Fine S, et al: Randomized trial
of cyclophosphamide, methotrexate, and fluorouracil chemotherapy added to
tamoxifen as adjuvant therapy in postmenopausal women with node-positive
estrogen and/or progesterone receptor-positive breast cancer: A report of the
National Cancer Institute of Canada Clinical Trials Group. Breast Cancer Site
Group. J Clin Oncol 15:2302-2311, 1997.
34. Anonymous: Effectiveness of adjuvant chemotherapy in
combination with tamoxifen for node-positive postmenopausal breast cancer
patients. International Breast Cancer Study Group. J Clin Oncol 15:1385-1394,
35. Crivellari D, Bonetti M, Castiglione-Gertsch M, et al:
Burdens and benefits of adjuvant cyclophosphamide, methotrexate, and
fluorouracil and tamoxifen for elderly patients with breast cancer: The
International Breast Cancer Study Groups Trial VII. J Clin Oncol 18:1412-1422,
36. Colleoni M, Price KN, Castiglione-Gertsch M, et al:
Mortality during adjuvant treatment of early breast cancer with
cyclophosphamide, methotrexate, and fluorouracil. Lancet 354:130-131, 1999.
37. Fisher B, Redmond C, Legault-Poisson S, et al: Postoperative
chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of
positive-node breast cancer patients aged 50 years and older with tumors
responsive to tamoxifen: Results from the National Surgical Adjuvant Breast and
Bowel Project B-16. J Clin Oncol 8:1005-1018, 1990.
38. Wils JA, Bliss JM, Marty M, et al: Epirubicin plus tamoxifen
vs tamoxifen alone in node-positive postmenopausal patients with breast cancer:
A randomized trial of the International Collaborative Cancer Group. J Clin Oncol
39. Glick JH, Gelber RD, Goldhirsch A, et al: Meeting
highlights: Adjuvant therapy for primary breast cancer. J Natl Cancer Inst
40. Aaltomaa S, Lipponen P, Eskelinen M, et al: Prediction of
outcome after first recurrence of breast cancer. Eur J Surg 158:13-18, 1992.
41. Ellis MJ, Hayes DF, Lippman ME: Treatment of metastatic
breast cancer, in Harris JR, Lippman ME, Morrow M, et al (eds): Diseases of the
Breast (2nd ed), pp 749-797. Philadelphia, Lippincott Williams & Wilkins,
42. Del Mastro L, Venturini M, Lionetto R, et al: Randomized
phase III trial evaluating the role of erythropoietin in the prevention of
chemotherapy-induced anemia. J Clin Oncol 15:2715-2721, 1997.
43. Hortobagyi GN, Theriault RL, Lipton A, et al: Long-term
prevention of skeletal complications of metastatic breast cancer with
pamidronate. Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol
44. Theriault RL, Lipton A, Hortobagyi GN, et al: Pamidronate
reduces skeletal morbidity in women with advanced breast cancer and lytic bone
lesions: A randomized, placebo-controlled trial. Protocol 18 Aredia Breast
Cancer Study Group. J Clin Oncol 17:846-854, 1999.
45. Cobleigh MA, Vogel CL, Tripathy D, et al: Efficacy and
safety of Herceptin (humanized anti-HER2 antibody) as a single agent in 222
women with HER2 overexpression who relapsed following chemotherapy for
metastatic breast cancer (abstract). Proc Am Soc Clin Oncol 17:97a, 1998.
46. Shak S: Overview of the trastuzumab (Herceptin) anti-HER2
monoclonal antibody clinical program in HER2-overexpressing metastatic breast
cancer. Herceptin Multinational Investigator Study Group. [Review] [21 refs].
Semin Oncol 26:71-77, 1999.
47. Burstein HJ, Kuter I, Richardson PJ, et al: Herceptin and
vinorelbine as second-line therapy for HER2-positive metastatic breast cancer.
Breast Cancer Res Treat 57:29, 1999.
48. Love RR, Anker G, Yang Y, et al: Serum homocysteine levels
in postmenopausal breast cancer patients treated with tamoxifen. Cancer Lett
49. Giovanazzi-Bannon S, Rademaker A, Lai G, et al: Treatment
tolerance of elderly cancer patients entered onto phase II clinical trials: An
Illinois Cancer Center study. J Clin Oncol 12:2447-2452, 1994.
50. Christman K, Muss HB, Case LD, et al: Chemotherapy of
metastatic breast cancer in the elderly. The Piedmont Oncology Association
experience. JAMA 268:57-62, 1992.
51. Begg CB, Carbone PP: Clinical trials and drug toxicity in
the elderly. The experience of the Eastern Cooperative Oncology Group. Cancer
52. Kimmick GG, Fleming R, Muss HB, et al: Cancer chemotherapy
in older adultsA tolerability perspective. Drugs Aging 10:34-49, 1997.
53. Begg CB, Elson PJ, Carbone PP: A study of excess hematologic
toxicity in elderly patients treated on chemotherapy protocols, in Yancik R
(ed): Cancer in the Elderly: Approaches to Early Detection and Management, pp
149-161. Springer-Verlag, New York, 1989.
54. Begg CB, Cohen JL, Ellerton J: Are the elderly predisposed
to toxicity from cancer chemotherapy? An investigation using data from the
Eastern Cooperative Oncology Group. Cancer Clin Trials 3:369-374, 1980.
55. Gelman RS, Taylor SG: Cyclophosphamide, methotrexate, and
fluorouracil chemotherapy in women more than 65 years old with advanced breast
cancer: The elimination of age trends in toxicity by using doses based on
creatinine clearance. J Clin Oncol 2:1404-1413,
56. Ibrahim NK, Frye DK, Buzdar AU, et al: Doxorubicin-based
chemotherapy in elderly patients with metastatic breast cancer. Tolerance and
outcome. Arch Intern Med 156:882-888,
57. Lichtman SM, Skirvin JA: Pharmacology of antineoplastic
agents in older cancer patients. Oncology 14:1743-1763, 2000.
58. Nerenz DR, Love RR, Leventhal H, et al: Psychosocial
consequences of cancer chemotherapy for elderly patients. Health Serv Res
59. Fossati R, Confalonieri C, Torri V, et al: Cytotoxic and
hormonal treatment for metastatic breast cancer: A systematic review of
published randomized trials involving 31,510 women. J Clin Oncol 16:3439-3460,
60. Joensuu H, Holli K, Heikkinen M, et al: Combination
chemotherapy vs single-agent therapy as first- and second-line treatment in
metastatic breast cancer: A prospecitive randomized trial. J Clin Oncol
61. Bishop JF, Dewar J, Toner GC, et al: Initial paclitaxel
improves outcome compared with CMFP combination chemotherapy as front-line
therapy in untreated metastatic breast cancer. J Clin Oncol 17:2355-2366, 1999.
62. Ibrahim NK, Hortobagyi GN, Ewer M, et al:
Doxorubicin-induced congestive heart failure in elderly patients with metastatic
breast cancer, with long-term follow-up: The M. D. Anderson experience. Cancer
Chemother Pharmacol 43:471-478, 1999.
63. Valero V, Buzdar AU, Theriault RL, et al: Phase II trial of
liposome-encapsulated doxorubicin, cyclophosphamide, and fluorouracil as
first-line therapy in patients with metastatic breast cancer. J Clin Oncol
64. Repetto L, Vannozzi MO, Balleari E, et al: Mitoxantrone in
elderly patients with advanced breast cancer: Pharmacokinetics, marrow, and
peripheral hematopoietic progenitor cells. Anticancer Res 19:879-884, 1999.
65. Ehninger G, Proksch B, Heinzel G, et al: Clinical
pharmacology of mitoxantrone. Cancer Treat Rep 70:1373-1378, 1986.
66. Albain KS, Green SR, Lichter AS, et al: Influence of patient
characteristics, socioeconomic factors, geography, and systemic risk on the use
of breast-sparing treatment in women enrolled in adjuvant breast cancer studies:
An analysis of two intergroup trials. J Clin Oncol 14:3009-3017, 1996.
67. Vogel C, O’Rourke M, Winer E, et al: Vinorelbine as
first-line chemotherapy for advanced breast cancer in women 60 years of age or
older. Ann Oncol 10:397-402, 1999.
68. Sorio R, Robieux I, Galligioni E, et al: Pharmacokinetics
and tolerance of vinorelbine in elderly patients with metastatic breast cancer.
Eur J Cancer 33:301-303, 1997.
69. Vogel C, Cobleigh M, Tripathy D, et al: First-line,
non-hormonal, treatment of women with HER2 overexpressing metastatic breast
cancer with Herceptin (trastuzumab, humanized anti-HER2 antibody) (abstract
275). Proc Am Soc Clin Oncol 19:71a, 2000.
70. Kuzar ME, Albain KS, Huntington MO, et al: A phase II trial
of docetaxel and Herceptin in metastatic breast cancer patients overexpressing
HER-2 (abstract 512). Proc Am Soc Clin Oncol 19:131a, 2000.
71. Trimble EL, Carter CL, Cain D, et al: Representation of
older patients in cancer treatment trials. Cancer 74:2208-2214, 1994.
72. Hutchins LF, Unger JM, Crowley JJ, et al:
Underrepresentation of patients 65 years of age or older in cancer-treatment
trials. N Engl J Med 341:2061-2067, 1999.
73. Kemeny M, Muss HB, Kornblith AB, et al: Barriers to
participation of older women with breast cancer clinical trials (abstract 2371).
Proc Am Soc Clin Oncol 19:602a, 2000.
74. Siminoff LA, Zhang A, Colabianchi N, et al: Factors that
predict the referral of breast cancer patients onto clinical trials by their
surgeons and medical onologists. J Clin Oncol 18:1203-1211, 2000.
75. McKenna RJ: Clinical aspects of cancer in the elderly:
Treatment decisions, treatment choices, and follow-up. Cancer 74:2107-2117,
76. Goodwin JS, Hunt WC, Samet JM: Determinants of cancer
therapy in elderly patients. Cancer 72:594-601, 1993.